tbuckley/cabot-search huggingface dataset:
TMET-12. HYPERPOLARIZED Δ- [1-13C] GLUCONOLACTONE IMAGING VISUALIZES TERT-ASSOCIATED CHANGES IN DYNAMIC PENTOSE PHOSPHATE PATHWAY METABOLISM IN GLIOBLASTOMA
Authors: Noriaki Minami, Donghyun Hong, Celine Taglang, Georgios Batsios, Anne Marie Gillepspie, Nicholas Stevers, Pavithra Viswanath, Joseph F Costello, Sabrina Ronen
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND TERT promoter mutations are a hallmark of glioblastoma (GBM). We recently reported that the expression of TERT and its upstream transcriptional factor, GABPB1, are strongly correlated with redox in GBM with TERT promoter mutations. However, further imaging biomarkers which visualize redox-associated metabolism and TERT expression are needed. Here we demonstrate that 13C magnetic resonance spectroscopy (MRS) of hyperpolarized δ-[1-13C] gluconolactone metabolism is a useful imaging tool to visualize changes in dynamic pentose phosphate pathway (PPP) metabolism that reflect TERT-associated changes in redox in GBM. METHODS U251 human GBM cells stably expressing shRNA targeting TERT or GABPB1 were compared to controls. Doxycyclin-inducible shTERT or shGABPB1 U251 cells were also examined. For in vivo studies, cells were injected into immunodeficient rat brains and tumors confirmed by T2-weighted MRI. δ-[1-13C] gluconolactone was polarized using a Hypersense DNP polarizer and injected into live cells or tumor-bearing rats. For cells 13C-MRS was acquired using a 500MHz Agilent spectrometer and analyzed using Mnova and Matlab software. For in vivo13C-MRS studies, spectra were acquired using a 3T Bruker scanner and a spectral spatial echo-planar spectroscopic imaging sequence. Spectral signal to noise was improved using Tensor denoising. Spectra were processed using a custom-written Matlab script. RESULTS Hyperpolarized 6-phosphogluconolactone (6PG), the metabolic product from δ-[1-13C] gluconolactone via the PPP, was significantly reduced in TERT or GABPB1 silenced cells compared to control cells in both U251 models. The positive correlation between TERT expression and 6PG level was confirmed by linear regression analysis. Hyperpolarized 6PG production in both tumor models was also significantly reduced in TERT or GABPB1-silenced tumors compared to controls. CONCLUSION We successfully visualized TERT-associated changes in dynamic PPP metabolism in a GBM model in cells and in vivo. Hyperpolarized δ-[1-13C] gluconolactone is a potential tool for monitoring TERT expression in GBM with TERT promoter mutations.
CSIG-01. EGFR AND AXL RECEPTOR TYROSINE KINASES DRIVE ONCOGENESIS BY LZTR1 MUTATION
Authors: Aram Ko, Mohammad Hasanain, Young Taek Oh, Fulvio D'Angelo, Danika Sommer, Brulinda Frangaj, Suzanne Tran, Franck Bielle, Bianca Pollo, Rosina Paterra, Karima Mokhtari, Rajesh Soni, Matthieu Peyre, Marica Eoli, Michel Kalamarides, Marc Sanson, Antonio Iavarone, Anna Lasorella
Journal: Neuro-Oncology (2022)

Abstract LZTR1, the substrate-specific adaptor of a CUL3-dependent ubiquitin ligase is among the most frequently mutated ubiquitin ligase coding gene in syndromic and sporadic human cancers including glioblastoma multiforme, in which approximately 27% of cases harbor inactivating mutations and copy number loss. However, both the identity of the protein substrates targeted by LZTR1-mediated ubiquitylation and the biological contexts regulated by specific LZTR1-substrate(s) interactions remain uncertain. Here, we combined biochemical and genetic studies to identify LZTR1 substrates and interrogated their tumor-driving function in the context of LZTR1 loss-of-function mutations and in a new conditional Lztr1 knockout mouse. Multiple screens converged on the receptor tyrosine kinases EGFR and AXL as LZTR1 interactors targeted for ubiquitin-dependent degradation in the lysosome by LZTR1-CUL3 complexes. Pathogenic mutations affecting LZTR1 failed to promote degradation of EGFR and AXL in human tumors. Mice harboring conditional deletion of the LZTR1 gene combined with loss of CDKN2A in the neural progenitor compartment generated peripheral nervous system tumors including schwannoma like and malignant peripheral nervous system tumors (MPNST). Tumors from the LZTR1-mutant mouse model accumulated very high levels of EGFR and AXL and exhibited potent and specific vulnerability to the combinatorial inhibition of EGFR and AXL kinases. These findings explain the mechanism of tumorigenesis associated with LZTR1 inactivation and offer a therapeutic strategy to patients affected by tumors carrying mutations of LZTR1.
BIOS-02. CLINICAL OUTCOMES OF OVER 600 PATIENTS WITH GLIOBLASTOMA TREATED AT A CANADIAN TERTIARY CENTER IN THE PAST 15 YEARS: A COMPARATIVE ANALYSIS WITH THE PIVOTAL STUPP TRIAL
Authors: Julien Rousseau, Sara-Maude Desforges, Gilbert Jabbour, Bernard Lemieux, Sarah Lapointe, Karl Bélanger, Robert Moumdjian, Romain Cayrol, Marie Florescu, Giuseppina Laura Masucci, France Berthelet, Émilie Lemieux-Blanchard, Jean-Paul Bahary
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma is the most common malignant primary central nervous system tumor in adults and is associated with a poor prognosis. The benefit of adding concomitant followed by adjuvant temozolomide to radiotherapy after maximal safe resection was demonstrated by Stupp and colleagues in 2005 and has since remained the standard of care. This regimen conferred a statistically significant benefit with a 2-year survival rate of 26.5% compared to 10.4% in patients treated with radiotherapy alone. Our primary goal was to retrospectively assess the clinical outcomes of patients with glioblastoma treated at our institution over the past 15 years by comparing the overall survival (OS) and progression-free survival (PFS) from our cohort to data from the pivotal trial. Our secondary objective was to create a comprehensive database with clinical and pathological information in order to identify predictive and prognostic factors. We reviewed the clinical records of patients treated for glioblastoma from January 2005 to November 2019 at our center. We extracted data on survival and calculated OS and PFS using the Kaplan-Meier method. 617 patient charts were reviewed, out of which 17 were excluded because of missing data. The remaining 600 patients were included. Baseline demographic information was similar to that of the Stupp cohort, with the exception of a larger proportion of patients aged 50 or above (76% versus 69%, respectively). The median OS at our center was 14.3 months, 95% confidence interval [12.8-15.2], which was comparable to that of the original trial (14.6 months [13.2-16.8]). PFS was better in our cohort at 6 months (74.2% [70.7-77.7] versus 53.9% [48.1-59.6]) and 12 months (36.3% [32.5-40.2] versus 26.9% [21.8-32.1]), and comparable thereafter. Our study confirms that the data from the Stupp trial are reproducible in a Canadian academic center setting. Our database will allow us to explore potentially new predictive factors.
NCOG-14. INTRAOPERATIVE COGNITIVE-LINGUISTIC MAPPING GUIDED BY VISUALIZATION OF GAMMA BAND MODULATION ELECTROCORTICOGRAMS: PROOF OF CONCEPT IN A PATIENT WITH LEFT TEMPORAL AND OCCIPITAL LOW-GRADE ASTROCYTOMA
Authors: Kyle Noll, Priscella Asman, Katherine Connelly, Israt Tasnim, Chandra Swamy, Chibawanye Ene, Tummala Sudhakar, Roxana Grasu, Ho-Ling Liu, Vinodh Kumar, Matthew Muir, Sarah Prinsloo, Hayley Michener, Jeffrey Wefel, Nuri Ince, Sujit Prabhu
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE Determine the feasibility and preliminary utility of a novel approach to intraoperative brain mapping guided by visualization of electrocorticography (ECoG) heat maps. METHODS A 39-year-old male with a biopsy-proven left posterior temporal and occipital WHO grade II IDH-mutant astrocytoma underwent awake craniotomy with intraoperative language mapping. Language mapping utilized a dual iPad stimulus presentation system (NeuroMapper) coupled to a portable real-time neural signal processing system capable of both recording cortical activity and delivering direct cortical stimulation in a closed-loop fashion. An ECoG grid (4x8 with 1cm pitch) which covered the majority of the left temporal lobe was used to assess oscillatory cortical activity during administration of language paradigms including object, action, auditory descriptive, and written descriptive naming. ECoG recording and cortical stimulation were synchronized with stimulus presentation via a photosensor attached to the patient-facing tablet. Gamma band modulations in response to language paradigms at each electrode were processed in real-time and visualized as heat maps in MATLAB/Simulink. Following recording and visualization, bipolar direct cortical stimulation from the grid was conducted for each neighboring electrode pair (up to an intensity of 6 mA) during administration of language tasks. RESULTS Despite mild fluent aphasia, a large set of reliable baseline stimuli were obtained for the language mapping paradigms. All naming paradigms resulted in strongest heat map activation at electrode 12 located in the anterior to mid superior temporal gyrus. During stimulation, consistent speech arrest was observed across all paradigms when stimulating electrode pair 11-12, indicating good correspondence with ECoG heat map recordings. Additionally, this region corresponded well with posterior language network representation via resting-state fMRI. CONCLUSION Intraoperative real-time visualization of task-based ECoG gamma band modulation is feasible and may help identify targets for direct cortical stimulation. If validated, this may improve the efficiency and accuracy of intraoperative language mapping.
RADT-13. CLINICAL OUTCOMES COMPARING RADIOSURGERY TECHNIQUES FOR MANAGING LARGE BRAIN METASTASES
Authors: Tugce Kutuk, Rupesh Kotecha, Ranjini Tolakanahalli, Haley Appel, Matthew Hall, D Jay Wieczorek, Yongsook Lee, Michael McDermott, Manmeet Ahluwalia, Alonso Gutierrez, Minesh Mehta, Martin Tom
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Large brain metastases (BM) are associated with poor local control with single-fraction radiosurgery (SRS) alone. We sought to compare outcomes with various alternative management strategies to assess disease control rates. METHODS Consecutive patients diagnosed with BM ≥ 2 cm in maximum diameter between 3/2019-2/2021 and treated at a single tertiary institution were included. Primary endpoints included freedom-from-local-failure (FFLF) calculated on a per-lesion basis from the date of initial intervention to local failure, and overall survival (OS). Kaplan-Meier analysis and the log-rank test were used. RESULTS 86 patients with 102 large BM met inclusion criteria. The median age was 66 years (range: 31-98), median KPS was 90 (50-100), and 57.8% were female. The most common primary tumor was lung in 40 (39.2%) lesions. The median tumor volume was 9.7 cm3 (2.1-35.5 cm3) and the median maximum tumor diameter was 3.3 cm (2.9-5.6 cm). 37 (36.3%) lesions were treated with staged-SRS, 31 (30.4%) with resection and postoperative-SRS, 21 (20.6%) with preoperative-SRS and resection, and 13 (12.7%) with fractionated-SRS (FSRS). Lesions treated with preoperative-SRS or postoperative-SRS were associated with higher rates of no- or stable-extracranial disease, and larger tumor volumes (preoperative-SRS: median 14.5 cm3 [4.2-33.1]; postoperative-SRS: 18.0 cm3 [2.5-35.5]; FSRS: 5.9 cm3 [2.1-24.6]; staged-SRS: 6.5 cm3 [2.2-27.8]).With a median follow-up of 15.6 months, 12 (11.8%) local failures and 42 (41.2%) deaths occurred. 1-year FFLF and OS for entire cohort were 85.6% (95% CI: 77.9-93.3%) and 64.4% (95% CI: 54.7-74.1%), respectively. The 1-year FFLF (p=0.542)/OS (p=0.043) rates were 94.1%/100% for preoperative-SRS, 84.0%/43.4% for staged-SRS, 81.8%/74.1% for FSRS, and 81.5%/63.4% for postoperative-SRS, respectively. CONCLUSION Although limited by patient numbers, selection bias, and high attrition rate, preoperative-SRS had the numerically most favorable outcomes, supporting this approach for large BM. Prospective evaluation is warranted to determine the optimal management strategy.
RADT-16. CLINICAL OUTCOMES FOR HIGH RISK WHO GRADE II GLIOMA PATIENTS TREATED WITH UPFRONT TMZ-BASED CHEMORADIOTHERAPY
Authors: Hosniya Zarabi, Robert Wicks, Gregory Russel, Dineth Banderage, Roy Strowd, Ryan Mott, Adrian Laxton, Stephen Tatter, Jaclyn White, Hui-Wen Lo, Waldemar Debinski, Michael Chan, Glenn Lesser, Christina Cramer
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE RTOG 9802 demonstrated improved survival using chemoradiotherapy (CRT) over radiotherapy (RT) alone for WHO Grade II gliomas (LGG) using PCV with RT. We analyze our retrospective dataset of predominantly temozolomide (TMZ)-based CRT in LGG patients who would have been eligible for RTOG 9802. METHODS Retrospective review of LGG patients (2000–2017) treated at a single institution (67 patients). Histologies included oligodendroglioma(OD), astrocytoma(AC) or astrocytoma (OA). Those who received upfront RT +/- chemotherapy were included. The CRT cohort (n=40) consisted primarily of TMZ (n=36) administered concurrently with RT. 27 patients received RT alone. RT for both cohorts consisted of a median dose of 54 Gy (range 50.4 - 54 Gy). 65/67 patients had “high risk” LGG as defined by RTOG 9802 criteria. Kaplan Meier analysis was used to assess overall survival (OS) and progression free survival (PFS). RESULTS 5-year PFS for patients receiving CRT was 64% vs. 44% in those receiving RT alone (log rank p=0.009). Difference in PFS due to chemotherapy was driven by AC histology (57% vs. 21% PFS at 5 years, log rank p=0.002) while OD/OA PFS was not statistically altered (79% vs. 72% PFS at 5 years, p=0.21). 5-year OS for patients receiving CRT was 76% vs. 69% in those receiving RT alone (p=0.11). Cox Proportional Hazards analysis showed that use of upfront CRT (HR=0.4, p=0.009) was the only factor that decreased the risk of earlier progression. CONCLUSION Use of upfront, predominantly TMZ-based CRT, has a PFS benefit over RT alone in a population of WHO grade II gliomas. This benefit appears to be driven by AC histology and also appears to extend beyond the “very high risk” cohort from RTOG 0424 to include the “high risk” group from RTOG 9802.
TMIC-68. EVALUATING FLASH AND CONVENTIONAL DOSE-RATE RADIATION AND IMMUNE RESPONSE WITH SINGLE-CELL SEQUENCING IN DIFFUSE MIDLINE GLIOMA (DMG)
Authors: Hanna Minns, Oscar Padilla, Hong-Jian Wei, Andrea Webster-Carrion, Masih Tazhibi, Nicholas McQuillan, Xu Zhang, Rebecca Yeh, Zhiguo Zhang, Luca Szalontay, Jovana Pavisic, Guy Garty, James Garvin, Peter Canoll, Claire Vanpouille-Box, Vilas Menon, Marta Olah, Raul Rabadan, Cheng-Chia Wu, Robyn Gartrell
Journal: Neuro-Oncology (2022)

Abstract Diffuse Midline Glioma – H3K27M mutant (DMG), is a fatal and inoperable pediatric brain tumor with limited treatment options as radiation provides only temporary reprieve, leaving the median survival between 9-15 months. Conventional dose-rate radiation (2Gray/minute, CONV) has been shown in other cancers to recruit an immune component, however, this has not been studied in DMG. Ultra-high dose-rate radiation given at 90 Gray/second (FLASH), is a novel technique associated with decreased toxicity and effective tumor control. Using a syngeneic model of brainstem DMG, we performed single-cell RNA sequencing on CD45+ immune cells isolated from tumors irradiated with 15Gray using FLASH or CONV, and compared to unirradiated tumor and normal brainstem. Isolation of 33,308 immune cells revealed 17 unique clusters, most abundant of which was microglia (73.8%), present in four distinct subtypes representing a spectrum from homeostatic to activated. In the most activated microglia, both FLASH and CONV showed an enrichment in type 1 interferon (IFN1) pathway scores compared to untreated tumors (p&amp;lt; 0.001 and p&amp;lt; 0.001, respectively). The most differential response was found in macrophages (MAC) and dendritic cells (DC) with a robust enrichment of IFN1 pathway scores for CONV compared to FLASH (p&amp;lt; 0.001, MAC and p&amp;lt; 0.001 DC). FLASH showed an increase in anti-inflammatory MAC markers such as Mrc1, Cd163, and Maf and an enrichment of myeloid-derived suppressor cell (MDSC) signature in monocytes, not seen in CONV (p&amp;lt; 0.001). Finally, we correlated our data with publicly available single-cell data taken from the cerebrospinal fluid of DMG patients treated with anti-GD2 CAR T Cell therapy and found similar inflammatory markers characteristic of our unirradiated murine tumors. In summary, our work is the first to study immune alterations comparing different dose-rates of radiation with single-cell resolution in DMG, highlighting the potential for combining radiation and immunotherapy in these tumors.
CCRG-01. KAT5 ACTIVITY REGULATES G0-LIKE STATES IN HUMAN GLIOMAS
Authors: Anca Mihalas, Sonali Arora, Samantha O'Connor, Heather Feldman, Anoop Patel, Patrick Paddison
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma, the most aggressive type of primary brain cancer, benefits little from standard of care therapy. Over the past few decades not much advancement has been made in improving the recurrence-free survival after treatment, with a median survival period of 15 month from diagnostic. G0-like states are thought to act a reservoir for tumor recurrence after treatment in glioblastoma. Targeting G0 states in glioblastoma poses an attractive therapeutic approach, however, little progress has been made in the field, likely due to poorly understood mechanisms that regulate G0 ingress and egress. To find regulators of G0 states, we performed a genome-wide CRISPR-Cas9 screen of patient-derived glioblastoma stem cells. We identified KAT5, a histone acetyltransferase coding gene which is the catalytic subunit of the histone acetyltransferase complex NuA4, as an important candidate for regulating G0 ingress and egress. We found that in primary gliomas, KAT5-low cells display G0-like properties, while overall KAT5 activity increases from low to high grade tumors. To study G0 states in glioblastoma, we have engineered an inducible KAT5 system that functions as a fully tunable model system, where we can control expression of KAT5 and, therefore, effectively control glioma cell entry and exit from G0-like states. We provide evidence that G0-like states are characterized by hypoacetylated histones and low protein synthesis rates, which remarkably induces shifts in cell state reminiscent of dedifferentiation and acquisition of stem-like behavior. Our work demonstrates that regulation of G0 like states may be coupled to the generation of tumor heterogeneity and, more importantly, suggests a potential strategy whereby inhibiting KAT5 activity could effectively "down grade" GBM tumors by lengthening residence time in G0-like states, significantly increasing survival times. For these studies we will present a variety of techniques, including single cell RNA-seq to characterize cellular subpopulations in tumors and GBM stem-like cell cultures.
NCOG-20. BRAIN ATROPHY IN GLIOBLASTOMA PATIENTS FOLLOWING TREATMENT WITH CHEMORADIATION OR CHEMORADIATION WITH ANTI-ANGIOGENIC THERAPY IN NRG/RTOG 0825 PARTICIPANTS
Authors: Oluwatosin Akintola, Jorg Dietrich, Alona Muzikansky, Melissa Gardner, Gilbert Youssef, Raymond Huang, Elizabeth Gerstner, Patrick Y Wen, Michael Parsons, Mark Gilbert, Leland Rogers, Frank Lieberman, Merideth Wendland, Vinay Puduvalli, Dennis Shrieve, Volker Stieber, Stephanie Pugh, Minesh Mehta
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND The clinical trial NRG/RTOG 0825 sought to determine if the addition of bevacizumab to temozolomide and radiation improves survival in patients with newly diagnosed glioblastomas. Tertiary objectives included measuring the effect of the addition of bevacizumab to standard chemoradiation on neurocognitive function and quality of life. In this study, we describe brain atrophy changes as measured by ventricular volume expansion. METHODS We analyzed longitudinal MRI brain studies obtained from NRG/RTOG-0825. Volume changes in the contralesional (non-tumor) lateral ventricle were measured. Patients were included if they had either a scan at post operative (week 0) or post radiation baseline (week 10). Patients were also required to have at least one follow-up MRI brain scan 6 months or more from their baseline scans (at Week 0 or Week 10). Volumes were delineated using tissue segmentation in Slicer software. RESULTS 177 patients were identified with eligible baseline scans at Week 0 and 162 patients at Week 10. For participants analyzed at 6 months from the Week 0 scan, mean ventricular volume increased by 54.70% (SEM: 3.21%, t = 6.41, p &amp;lt; 0.001, N = 135). For patients analyzed at 6 months from the Week 10 scan, mean ventricular volume increased by 31.89% (SEM: 2.52%, t = 3.96, p &amp;lt; 0.001, Nf117). CONCLUSIONS This study presents evidence of progressive brain volume loss in patients with glioblastoma treated with standard chemoradiation with or without anti-VEGF therapy. This is one of the largest sample sizes of volumetric analysis in real world patients with glioblastoma. These volume changes begin early in the disease course and may precede treatment. Next directions include correlating these volumetric changes with neurocognitive score changes, quality of life scores and analyzing these changes by treatment arm.
NCOG-03. IMPACT OF THE RATE OF RADIOGRAPHIC RESPONSE (RR) OF BRAIN METASTASES (BM) TO WHOLE BRAIN RADIATION THERAPY (WBRT) ON NEUROCOGNITIVE FUNCTION (NCF) ON NRG-CC001
Authors: Kiran Devisetty, Stephanie Pugh, Paul Brown, Vinai Gondi, Jeffrey Wefel, Abhishek Solanki, Tomy Kalapparambath, Grant Harmon, Anjali Saripalli, Brian Chou, Bhanu Prasad Venkatesulu, Thomas Boike, Vijayananda Kundapur, David Roberge, Joseph Bovi, Mackenzie McGee, Tim Kruser, Andrew Baschnagel, Kenneth Usuki, Minesh Mehta, Lisa Kachnic
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND The assessment of BM response to WBRT and its impact on NCF in clinical trials has been limited by lack of standardized imaging protocols. NRG-CC001 is a randomized clinical trial requiring pre-specified MRI protocols at baseline and 6-months, providing a uniform dataset to investigate if RR correlates with NCF changes. METHODS NRG-CC001 randomized patients with BM to hippocampal avoidance WBRT (HA-WBRT) or WBRT. NCF was analyzed using 6-month standardized change scores and deterioration, defined using the reliable change index. Chi-square and t-tests were used for pretreatment characteristic comparisons. Inter-rater reliability between central and institutional assessment of RR was assessed with weighted kappa, κ. Linear regression was used to test trends in NCF change scores across types of response and multivariable logistic regression was used to test the association of RR to NCF deterioration. RESULTS 149 and 135 patients were evaluable for RR and NCF assessment, respectively. Pretreatment characteristics were well-balanced, except for post-high school education (70.6% HA-WBRT vs. 52.5% WBRT, p=0.023). Inter-rater reliability between central and institutional assessment of RR was fair (κ=0.36). There was no difference between arms in RR (p=0.41) with overall rates of 14.1% CR, 42.2% PR, 17% SD, and 26.7% PD. Patients with CR had improved 6-month NCF change as measured by HVLT-R Total Recall (p=0.0005), HVLT-R Delayed Recall (p=0.0003), HVLT-R Delayed Recognition (p=0.011), TMT-B (p=0.033), COWA (p=0.016), and Clinical Trial Battery Composite score (p=0.0011). Multivariable analysis demonstrated less deterioration in HVLT-R Delayed Recall for CR (p=0.019) and PR (p=0.0086) vs. SD/PD and HVLT-R Recognition for PR (p=0.031) vs. SD/PD. CONCLUSIONS HA-WBRT and WBRT result in similar RR at 6-months. CR or PR is associated with better NCF preservation. This suggests investigation into treatment escalation for patients with SD/PD may provide further NCF benefit along with HA-WBRT and memantine.Grant support from NCI-UG1CA189867 and U24CA180803.